Cardiovascular disease is a symptom of heart and blood vessels. Cardiovascular disease can be grouped as coronary artery heart disease, cerebrovascular disease, peripheral arterial occlusion disease, rheumatic heart disease, congenital heart disease, deep vein thrombosis and pulmonary embolism. Ischemic heart disease, myocardial infarction or sudden death will be induced if coronary arteriosclerosis occurs. The occurrence of cerebral or carotid arteriosclerosis will result in renal hypertension and even uremia. Peripheral arteriosclerosis will result in aneurism or atherosclerosis obliterans. Therefore, arteriosclerosis is closely associated with cardiovascular diseases.
The causes of atherosclerosis are hyperlipidemia or hemagglutination. For instance, lipopolysaccharide (LPS) activates cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and further stimulates the proliferation of smooth muscle cells and increases the generation of adhesion factors. In addition, LPS will interact with toll-like receptor (TLR4) region on endothelial cells or macrophages, and then activates nuclear factor-kappa B (NF-κB) and p44/p42 mitogen-activated protein kinase (MAPK) pathways. Accordingly, inflammation induced by LPS will result in arteriosclerosis.
Atherosclerosis belongs to an inflammation, and the damaged vascular endothelial cells will result in hindrance of vascular endothecium and changes of permeability. Abundant low density lipoprotein (LDL) enters into endothelial cells, and oxidized-LDL (Ox-LDL) is reproduced to stimulate endothelial cells or smooth muscle cells to generate chemotaxis materials, which attract monocytes entering into the lower space of endothelial cells, and monocytes are transformed as macrophages which engulf Ox-LDL to form foam cells. The accumulation of a plenty of foam cells enhances cytokines, growth factors and prostagladin. Cytokines stimulates the proliferation of smooth muscle cells in the mesoderm of vessels, and smooth muscle cells are moved to endoderm to divide/proliferate and reproduce collagenous fibers to form plaques, attract the adhesion and aggregation of platelets, and form thrombus to block the blood flow, so that the acute diseases such as the unstable angina cordis, the acute myocardial infarction and stroke etc. occur in clinics.
Currently, the drugs for treating atherosclerosis usually are antilipemic agents or antithrombotic agents.
The antilipemic agents are divided as four groups, bile acid sequestrant resin, fibric acid derivative, nicotinic acid derivative and statin drug. (1) The bile acid sequestrant resin blocks bile acid in the gastrointestinal tract from absorption, increases the compensation of liver to reproduce bile acid using cholesterol and reduces the amount of cholesterol in the liver cells. However, the side effect of stomach upset (diarrhea or constipation) might occur. (2) The fibric acid derivative decreases the concentration of triglyceride in the blood, and it might induce the side effects such as gripes, diarrhea, nausea, vomit, the upgrade of liver function indexes and so on. (3) Nicotinic acid derivative is capable of reducing the concentrations of LDL, triglyceride and cholesterol, and is capable of increasing the concentration of high density lipoprotein (HDL). Nevertheless, the side effects such as stomach upset, hyperuricacidemia, gout, exanthema and the upgrade of liver function indexes and so on would occur. The probability of gallstones might be increased due to a long term administration. (4) Statin drug is the most effective and the most common antilipemic agent, which inhibits the rate-limited enzyme for cholesterol synthesis in liver cells and further reduces the amount of cholesterol in the blood. The side effects includes the upgrade of liver function indexes, headache, gripes and weariness, etc.
Antithrombotic agents are divided as three groups, anticoagulant, antiplatelet drug and thrombolytic agent. Anticoagulant further is divided as four sub-groups, vitamin K antagonist, heparin and its derivative, direct thrombin inhibitor and other anticoagulant drugs. (1) Vitamin K antagonist includes Warfarin (also is a pesticide against rats and mice), dicoumarin and so on. Its chemical structure is similar to that of vitamin K, and its functional mechanism is to counteract the activity responses of vitamin K-dependent coagulation factors II, VII, IV and X. However, Vitamin K antagonist will result in the side effects such as hematuria, gastrointestinal bleeding, intracerebral hemorrhage and so on. (2) Heparin is composed of D-glucamine interacting with L-iduronic acid and D-glucuronic acid. Heparin is conjugated with the anti-coagulation factor III first, and then accelerates thrombin inactivation to achieve anti-coagulation. Heparin also can be conjugated with a plenty of coagulation factors such as IIa, Xa, XIa and XIIa, to inactivate coagulation factors. However, heparin might generate the side effects such as bleeding, hypersensitivity, platelet deficiency disease and so on. (3) Direct thrombin inhibitor includes hirudin and bivalirudin, etc., wherein hirudin is a 65-amino acid protein which is obtained from the salivary gland of leech and plays the critical role in hemostasis and inhibition of thrombus formation. Although hirudin is the most effective natural anticoagulant, it is difficult to extract it from leeches and hirudin must be prepared with the recombinant biotechnology. (4) The examples of other anticoagulant drug includes ramatroban which is a thromboxane receptor inhibitor.
Antiplatelet drug further is divided as five sub-groups, COX inhibitor, adenosine diphosphate (ADP) receptor inhibitor, phosphodiesterase (PDE) inhibitor, adenosine reuptake inhibitor and thromboxane inhibitor.
Among COX inhibitors, aspirin (low dosage) can inhibit platelet aggregation and prevent thrombosis formation. Since aspirin will reduce the secretion of protection materials in stomach, so that side effects, e.g. stomach upset, gastrointestinal bleeding and so on, would occur. Among ADP receptor inhibitors, Clopidogrel would have the risk of stomach bleeding. Among PDE inhibitors, Cilostazol could inhibit phosphodiesterase (PDE) activity (especially selectively to PDE III) and impede the cyclic adenosine monophosphate (cAMP) metabolism in cells, and promote the increase of cAMP concentration in platelets and vessels. Thus, Cilostazol has the functions of anti-platelet aggregation and angiectasis, but results in side effects such as headache, diarrhea, vomit, erythematous rash, and hematological abnormality, etc. Among adenosine reuptake inhibitors, dipyridamole could inhibit platelet aggregation caused by platelet activation factors, collagen, ADP and so on, and it side effects are vertigo, dizziness, fainting, flame, headache, vomit, emesis, exanthema on skin, gripes and weakness, etc. When dipyridamole is administered with heparin, bleeding risk would be increased. Among thromboxane inhibitors, Terutroban can block platelet aggregation and vasoconstriction induced by thromboxane, promote endoderm's functions and has anti-atherosclerosis effect, whereas it also has the bleeding risk.
The efficacies of thrombolytic agent lie in activating plasmin and promoting fibriolysis. Thrombolytic agent is suitable for treating deep vein thrombosis, pulmonary embolism, acute myocardial infarction and acute arterial embolism, but it will result in bleeding and hypersensitivity.
Since the aforementioned two classes of atherosclerosis therapeutic drugs have different chemical structures and will generate plural side effects, developing new drugs in treatment of atherosclerosis and avoiding the generation of side effects become the important issues.
It is therefore attempted by the applicant to deal with the above situation encountered in the prior art.